This chapter is (barely) relevant to Section G8(iv)  of the 2017 CICM Primary Syllabus, which asks the exam candidate to "understand the pharmacology of antiarrhythmic drugs".  These are a favourite of the college. For a variety of fairly commonsense reasons, there is an emphasis on testing the trainee's understanding of these drugs, as they are at the same time common, powerful, dangerous, and often poorly understood.  However, historical CICM examiner focus has been interestingly narrow: 

  • Question 14 from the first paper of 2019 (digoxin vs. sotalol)
  • Question 2 from the second paper of 2018 (amiodarone vs digoxin)
  • Question 11 from the first paper of 2016 (amiodarone side effects)
  • Question 13 from the second paper of 2014 (amiodarone)
  • Question 9 from the second paper of 2012 (classification with a focus on Class 1 agents)
  • Question 22 from the second paper of 2010 (amiodarone vs digoxin)
  • Question 5 from the second paper of 2009 (digoxin)
  • Question 5 from the second paper of 2008 (amiodarone)

Do you notice a trend here? There is clearly some thirst among the examiners for a) certain iodinated compounds and b) cardiac glycosides. Owing to this clearly preferential treatment, each of these drugs has been given a chapter of its own, all the better to be familiar with their properties. The other agents have been piled unceremoniously into the wastebasket chapter below, mainly because the topic of antiarrhythmic classification has only ever appeared in one SAQ.  What follows is a merciless oversimplification of a fascinating topic, but even this is probably excessive, as the college clearly just wanted people to earn three marks by dumbly listing the Vaughan Williams classes.

Oh well:

  • Vaughan Williams classification of antiarrhythmic agents:
    • Class I: fast sodium channel blockers:
      • Class Ia: prolong the action potential (eg. quinidine)
      • Class Ib: shortens the action potential (eg. lignocaine)
      • Class Ic: no effect on the action potential (eg. flecainide)
    • Class II: Beta-blockers (eg. metoprolol)
    • Class III: Potassium channel blockers (eg. sotalol and amiodarone)
    • Class IV: calcium channel blockers (eg. verapamil and diltiazem)
  • Antiarrhythmic effects and the agents that exert them:
    • Reduction of pacemaker automaticity: agents which decrease the calcium currents in pacemaker cells, i.e. Class II and Class IV agents
    • Reduction of abnormal automaticity: agents which decrease the membrane resting potential in ventricular myocytes, i.e. mainly Class II agents
    • Reduction of early afterdepolarisations: agents which reduce the action potential and repolarisation duration, i.e. Class II and Ib agents
      • Some agents actually increase early afterdepolarizations by delaying repolarisation
      • These are the same agents that prolong the QT interval (i.e. Class Ia and Class III agents)
    • Reduction of delayed afterdepolarisations:
      • Agents which decrease the availability of intracellular calcium (i.e. Class II and IV agents)
      • Agents which decrease the availability of intracellular sodium (i.e. Class I agents)
    • Reduction of reentry currents:
      • Agents which slow AV nodal conduction (i.e. adenosine, digoxin, Class II and Class IV agents)
      • Agents which slow the velocity of conduction (i.e. Class Ia and Ic agents)
      • Agents which increase the refractory period (i.e Class III, Ia and Ic agents)

Realistically, the revising exam candiate would find that the Part One entry contains all the essential information required to pass these SAQs. It also helps that it is presented in a highly condensed form, free from verbal greebles and nurnies. For something published in a respectable journal (i.e. one which you have to pay to get published in), one could use something like Capucci et al (1998). This probably represents some sort of maximum of what a normal exam candidate should be expected to absorb. On the other hand, for the reader with an infinite capacity for minute pharmacological detail, the 1998 report by Carmeliet & Mubagwa will satisfy even the hungriest brain parasites. It is 72 pages long, and dense like a neutron star. 

Classification systems for antiarrhythmic agents

For the purposes of studying for the CICM First part exam, there is really only one system. One might occasionally hear it being referred to as the "Vaughan and Williams" or "Vaughan-Williams" classification, which is, of course, inaccurate because it is named after Miles Vaughan Williams, the celebrated pharmacologist and ninety-year-old fitness guru. His classification system was first presented in April of 1970, at the Symposium on Cardiac Arrhythmias in Elsinore, Denmark (yes, that Elsinore). The original 826-page symposium is not available electronically, and the nearest physical copy lays 110km north of the author, at the University of Newcastle Auschmuty Library. Fortunately, five years later, it was incorporated into a textbook, through which archaeologists can discern its original shape. 

  • Class I: drugs which "interfere directly with depolarization", eg. quinidine
  • Class II: drugs with "antisympathetic action", eg. beta-blockers
  • Class III:  drugs which "prolong the duration of the action potential", eg amiodarone

It seems like a possible fourth class was also being considered in 1975, as verapamil had recently appeared onto the scene and had clearly demonstrated antiarrhythmic properties. However, it was not formally added at this stage.  In fact, like everything that gets incorporated into a textbook, this three-class system turned out to be extremely tenacious and remained basically unchanged well into the 1980s even as novel agents were developed and new physiology research had come to light.  The next reassessment of the Vaughan Williams classification was his own (1984), where he rephrased the class definitions, added calcium channel blockers, and further subdivided Class I into Ia, Ib and Ic on clinical grounds:

  • Class I: fast sodium channel blockers:
    • Class Ia: prolong the action potential (eg. quinidine)
    • Class Ib: shortens the action potential (eg. lignocaine)
    • Class Ic: no effect on the action potential (eg. flecainide)
  • Class II: Beta blockers (eg. metoprolol)
  • Class III: Potassium channel blockers (eg. sotalol and amiodarone)
  • Class IV: calcium channel blockers (eg. verapamil and diltiazem)

However, the modern reader will readily point out that not only do we have multiple other agents currently used to treat or prevent arrhythmias, but there are also many agents which were already well established in he 1980s (eg. digoxin) which seem to be unfairly omitted from this classification system. Moreover, many among the listed drugs have multiple effects across multiple classes (famously, amiodarone).  In response to these shortcomings, Rosen & Schwartz (1991) offered to reclassify antiarrhythmic drugs without trying to pigeonhole them into limiting categories. They called their system "The Sicilian Gambit",  in reference to an opening chess move which involves the sacrifice of pieces in order to achieve a strategic advantage. Confusingly, they called it "Sicilian" because the European Societ of Cardiology met in Sicily that year, and not because of the Sicilian defence which is another popular opening move.  These random details notwithstanding, the authors had a rather noble purpose: to bring the classification of antiarrhythmics out of its Vaughn Williams disarray, and to present the agents in a spreadsheet which illustrates their multiple simultaneous effects, like so:

the Sicilian Gambit classification of antiarrhythmic agents

Unfortunately, judging by the limited acceptance of this schema, it appears that everybody else had preferred disarray.  To illustrate how much this is the case, one is directed to the last entry into this saturated field, made by Lei et al (2018), on the centenary of M. Vaughan Williams'  birth. Their system is well-reasoned, comprehensive, inclusive of all existing agents, and therefore unwieldy and awkward:

  • Class 0: Sinoatrial node blockers
    • Just one subclass, and one member - ivabradine
  • Class I: voltage-gated sodium channel blockers
    • Class Ia: intermediate-dissociating Na+ channel blockers, eg. quinidine
    • Class Ib: fast-dissociating Na+ channel blockers, eg. lignocaine
    • Class Ic: slow-dissociating Na+ channel blockers, eg. flecainide
    • Class Id: late Na+ current blockers, eg. ranolazine
  • Class II: Autonomic inhibitor and activators
    • Class IIa: non-selective β-blockers, eg. propanolol
    • Class IIb: non-selective β-agonists, eg. isoprenaline
    • Class IIc: Muscarinic M2 receptor inhibitors, eg. atropine
    • Class IId: Muscarinic M2 receptor agonists, eg. digoxin
    • Class IIe: Adenosine A1 receptor agonists, eg. adenosine
  • Class III: Potassium channel blockers and openers
    • Class IIIa: nonselective K+ channel blockers, eg. amiodarone and sotalol
    • Class IIIb: metabolically dependent K+ channel blockers, eg. nicorandil
    • Class IIIc: transmitter dependent K+ channel blockers (none available)
  • Class IV: Ca2+ handling modulators
    • Class IVa: nonselective Ca2+ channel blockers (eg. verapamil and diltiazem)
    • Class IVb: intracellular Ca2+ channel blockers (eg. flecainide, propafenone)
    • Class IVc: sarcoplasmic reticular Ca2+ pump activators (none available)
    • Class IVd: membrane Ca2+ exchange inhibitors (none available)
    • Class IVe: Cytosolic Ca2+ handling protein phosphorylators (none)
  • Class V: mechanosensitive channel blockers  (none currently available)
  • Class VI: gap junction channel blockers (none curently available)
  • Class VII: upstream target modulators  (ACE-inhibitors, statins, omega-3 fatty acids)

This system is reproduced here mainly because of the authors' fondness for awkward things, and in the hope that it one day finds more recognition than it currently has. One must remember that the official college textbook (and basically all the other influential material on this topic) were published before 2018 and will therefore be parroting the 1984 version of the Vaughan Williams classification. Moreover, many of the CICM Part I examiners will have trained during this time period and will have some nostalgic fondness for the old system. Therefore, the trainee is advised not to startle these people with any unnecessarily modern concepts. One should not present oneself as a dangerous radical anarchist during one's pharmacology viva. It is in this counterrevolutionary spirit that the rest of this discussion will be conducted.

Anyway.  From the emphasis on mechanisms of action which is inherent in this classification system, it follows that the only logical way to systematically discuss these agents is to start with their pharmacodynamic properties, and to handle the boring pharmacokinetics as an afterthought and shadow. This would be fairly consistent with college expectations, as they really only ever seemed interested in the ADME of amiodarone and digoxin, and those are handled separately.

Origins and mechanisms of arrhythmic and antiarrhythmic effects

To paraphrase the entire chapter dealing with abnormal cardiac electrical activity, as well as Grant (1992) and Barrio-Lopez (2020), arrhythmias arise because of:

  • Abnormal automaticity, where some normal tissue becomes overexcited and decides to become a pacemaker, or existing pacemakers make pace in some disorganised or abnormal manner.
  • Early afterdepolarisations, triggered depolarisations which occur during Phase 3, and which are promoted by anything which prolongs the repolarisation
  • Late afterdepolarisations, triggered depolarisations which occur during Phase 4, and which are promoted by anything that might increase the intracellular calcium
  • Reentry, where acton potential re-excites a patch of myocardium shortly after it has already depolarised, either because of some anatomical shortcut or because of an abnormally short refractory period

From this, it follows that antiarrhythmic effects should address these proarrhythmic mechanisms in some way. And indeed they do, but not in a way which makes them any easier to categorise. Many drugs with antiarrhythmic properties address several of these mechanisms simultaneously, and others may actually promote arrhythmias by prolonging repolarisation (those would be all the antiarrhythmics which prolong the QT interval). Still, it is possible to vaguely relate arrhythmogenic and antiarrhythmic mechanisms, as follows:

  • Abnormal automaticity of normal pacemakers: it sounds like this would respond to anything that decreases the slope of Phase 4 in those cells, which would be calcium channel blockers and β-blockers
  • Abnormal automaticity of non-pacemaker tissue should decrease as the result of beta-blockade. Reduced resting potential voltage of the membrane is usually the main problem, which these drugs should address.
  • Late afterdepolarisations, where the problem is catecholamines or calcium, are addressed directly by calcium channel blockers and β-blockers
  • Reentry, where action potential re-excites a patch of myocardium shortly after it has already depolarised, either because of some anatomical shortcut or because of an abnormally short refractory period. You can prolong the latter using Class Ia and Class III agents. As for abnormal conducting pathways, the best mechanism of managing this would be to slow conduction through those fibres, and this is where Class Ic agents should be ideal.

Now, for each class, some sort of short point-form summary of pharmacodynamic properties will be attempted, mainly in case one day these drugs become the topic of an SAQ. This has already happened to Class I agents in Question 9 from the second paper of 2012, which means that these are probably fair game. 

Class I antiarrhythmic agents: sodium channel blockers

Class I agents are sodium channel blockers. They generally bind to a site inside the pore of the Nav1.5 subunit of the fast voltage-gated sodium channel, which is responsible for Phase 0 of the cardiac action potential. All prefer to bind to open or inactivated sodium channels (though the slowly dissociating Class Ic agents remain bound even when the channels return to their resting state). Speaking of which, this class is further subdivided into subclasses according to what the drugs do to the action potential and what dissociation kinetics they have: 

  • Class Ia agents, eg. quinidine and procainamide
    • Have an intermediate dissociation rate
    • Prolongs the duration of the action potential (mainly by their potassium channel blocker effects)
    • Therefore, prolong the QT interval
    • Prolong the QRS complex because of a longer Phase 0
    • Use-dependence: block effect (and QRS prolongation) is more pronounced in tachycardia because of slower dissociation from the binding site in diastole
  • Class Ib agents, eg. lignocaine and mexelitine
    • Dissociate rapidly from the binding site, therefore free from use dependence
    • Have no effect on the duration of Phase 0
    • Therefore, do not prolong the QRS
    • Shorten the duration of the action potential, mainly by preventing late sustained sodium current
    • Therefore, shorten the QT interval
  • Class Ic agents, eg. flecainide and propafenone
    • Dissociate slowly from the binding site, which means there is no use-dependence
    • Prolong Phase 0 more than other subclasses
    • Therefore, prolong the QRS duration
    • Have little effect on the duration of the action potential and therefore do not prolong the QT interval

The antiarrhythmic effect is felt in multiple ways:

  • Automaticity of normal pacemakers should remain abnormal while you are on a Class I agent. Phase 4 of normal pacemaker cells does in fact depend on sodium currents (the "funny current", targeted by ivabradine), but those channels are distinct from the vast voltage-gated ones, and are not affected by Class I agents. Therefore, they generally don't tend to act as rhythm control agents for AF (for example). However, various reputable sources claim that they can still affect the slope of Phase 4 "by mechanisms not understood and unrelated to blocking fast sodium channels". Famously, flecainide has been used to suppress atrial fibrillation, and we still don't know how it exerts this effect (Echt & Ruskin, 2020). 
  • Abnormal automaticity of non-pacemaker tissue should also remain unchanged, but it apparently decreases. It is also mentioned in various papers, but without much further explanation or reference. This is strange, as most people tend to think of Class I agents as anti-VT or anti-VF drugs.
  • Early afterdepolarisations can actually increase in the context of Class I agent use, particularly with Class A agents which prolong the repolarisation. Like other QT-prolonging drugs, they can produce polymorphic VT. 
  • Late afterdepolarisations should theoretically decrease in the context of sodium channel blockers, as they decrease the amount of intracellular sodium available for the sodium/calcium exchanger, which should theoretically mean less intracellular calcium being available (and it is the latter that is responsible for these phenomena). However, experimentally, this does not appear to be the case.
  • Reentry is really where these agents are most effective. By decreasing the velocity of conduction, these agents slow the propagation of action potentials along the abnormal conducting pathways and therefore prevent reentrant tachycardias such as SVT. For this, Class Ic agents are ideal (for instance, flecainide is used to prevent arrhythmias in Wolff-Parkinson-White syndrome).

Class II antiarrhythmic agents: β-blockers

There is also a sub-classification of beta-blockers, one of which can be mentioned here:

  • Non-selective
    • Propanolol
  • β1-selective
    • Atenolol
    • Metoprolol
    • Bisoprolol
    • Nebivolol
    • Esmolol
    • Sotalol
  • Combined α- and β-blocker effect
    • Carvedilol
    • Labetalol

Though most of the antiarrhythmic effect comes from their β1 effects, one needs to mention that some of these drugs have sodium channel blocker properties (propanolol) and others block potassium channels (sotalol).  However, they do not need those effects. Beta blockade has a rather diverse and potent effect on multiple cardiac ion channels, as listed in this table paraphrased from Dorian (2005):

Effect of Beta Blockers on Cardiac Ion Currents
Ion channel Effect of beta-blockade
INa fast inward sodium current Reduced current
Ito early, transient inward (repolarising) potassium current; Reduced current
ICa,L L-type inward calcium current Reduced current
INa/Ca  sodium/calcium exchange current Reduced current
Iti  transient inward current Reduced current
IK1 inward rectifier potassium current Increased current
IKs  slow delayed rectifier potassium current Reduced current
IKr  rapid delayed rectifier potassium current Increased current
If  pacemaker current (sodium) Reduced current

So, from a glance at this, one might surmise that beta-blockade favours rapid repolarisation of the membrane, supports currents which maintain its polarity, and opposes currents which promote depolarisation. Again from Dorian (2005), this slightly altered diagram of the beta-blocked cardiac action potential illustrates the net effect of these ion current changes:

effect of beta blockers on the cardiac action potential

So, how does this affect arrhythmogenicity? In summary:

  • Automaticity of normal pacemakers should decrease while under the effect of beta-blockers, as catecholamines are one of the main stimulants of this phenomenon. By lowering the membrane potential during Phase 4, these drugs increase the time required to reach the depolarisation threshold.
  • Abnormal automaticity of non-pacemaker tissue should also decrease, as beta-blockers are seen to reduce the appearance of ventricular ectopic beats. This is mainly because of the lower resting membrane potential.
  • Early afterdepolarisations are reduced because the repolarisation time and the overall action potential duration is reduced; this basically counteracts the proarrhythmic effect of QT-prolonging Class III agents, which is handy because many of them have pronounced beta blocker effects.
  • Late afterdepolarisations, which are mainly related to intracellular calcium excess, tend to improve with anything that counteracts the effect of catecholamines (as they increase intracellular calcium concentrations).
  • Reentry is often unaffected, as conduction velocity is largely unchanged in the presence of beta-blockade. The only exceptions may be specialised tissues such as the AV node, where unopposed vagal effects lead to conduction delay. Theoretically, that could defeat SVT.

Class III agents: potassium channel blockers

Amiodarone sotalol ibutilide and vernakalant are really the main contenders here, though worldwide there is an even larger selection of these agents available. This class prolongs repolarisation by interfering with the function of inward rectifier and outward delayed rectifier potassium currents, increasing the duration of the refractory period and of the action potential as a whole.

It is hard to discuss the Class III effects because the poster child for this class is amiodarone, and it acts promiscuously on all Class I-IV molecular targets. In fact, all Class III agents have some kind of extra weirdness (sotalol is a beta-blocker, ibutilide acts on slow inward depolarising sodium currents, etc). A "pure" potassium channel blocker effect is therefore difficult to describe using an example. Strictly speaking, they should only prolong repolarisation. The best resource to explain this would probably be the little fragment from Cardiac Electrophysiology: From Cell to Bedside (p. 518 of the 2017 edition). In short, these drugs mainly block Ikr, Iks and Ik1 currents which are responsible for Phase 3 of the cardiac action potential. Class III drugs are not unique in the effect, as there are many other drugs which interfere with this current (notably, macrolide antibiotics and antipsychotic drugs). One might say that some drugs prolong the QTc as an accidental side effect, but Class III agents do it intentionally. In the form of a diagram, one would express  this like so:

action potential changes due to Class III antiarrhythmics

So, 

  • Automaticity of normal pacemakers should remain more or less the same with a "pure" potassium blocker effect, but because amiodarone and sotalol have potent beta-blocker effects, these drugs are generally seen to slow the pacemaker rate.
  • Abnormal automaticity of non-pacemaker tissue should also remain unchanged, but it probably increases, mainly because of early afterdepolarisations. Fortunately, most of these drugs have enough beta-blocking activity to counteract this.
  • Early afterdepolarisations, which are mainly related to prolonged repolarisation, tend to increase because of a prolonged repolarisation time.
  • Later afterdepolarisations due to a calcium-based mechanism are largely unaffected by Class III agents. 
  • Reentry would be expected to decrease, as the prolonged effective refractory period should protect myocytes from adjacent ectopic pacemakers firing randomly.

Class IV agents: calcium channel blockers

Verapamil and diltiazem are the only real representatives here, as these are non-selective agents, whereas the dihydropyridine subclass tends to only affect the calcium channels in the vascular smooth muscle. Walker & Chia (1989) offer a good summary of their antiarrhythmic effects. In brief, their main effects are on pacemaker tissue, and on Phase 2 of the cardiac action potential. 

  • Automaticity of normal pacemakers decreases with calcium channel antagonists, as they decrease the rate of Phase 0 rise in pacemaker cells (recall that their more gradual Phase 0 is purely due to L-type calcium channel opening). 
  • Abnormal automaticity of non-pacemaker tissue should probably remain unchanged, as it is less reliant on calcium-mediated mechanisms. With this, calcium channel blockers should not be expected to control VT. 
  • Early afterdepolarisations should be reduced by calcium channel blockers, as these are mainly related to prolonged repolarisation, and calcium channel blockers shorten repolarisation by decreasing the duration of Phase 2. 
  • Later afterdepolarisations due to a calcium-based mechanism are the main course, and calcium channel blockers address their mechanism directly, by limiting the amount of available intracellular calcium
  • Reentry would be expected to remain unaffected, except for the effect of calcium channel blockers on the performance of nodal tissue. AV nodal and atrial bundle tissue conduction should decrease, and this could put an end to SVT. 

Other and Misc

At risk of being seen to promote the apostate classification system by Lei et al (2018), one needs to tentatively recognise that there are other drugs out there (digoxin, magnesium, adenosine, etc) which do not fit neatly into the Vaughan Williams classification. 

  • Digoxin and the other cardiac glycosides mainly exert their antiarrhythmic effects by a vagomimetic action on the AV node, where they slow the conduction of action potentials. By increasing the availability of intracellular calcium, digoxin may lead to an increased risk of late afterdepolarisations. Other than that, it has no real positive effect on the arrhythmogenesis of ventricular myocardium (Gbadebo et al, 2000)
  • Adenosine can be described as an antiarrhythmic by virtue of the fact that we only tend to use it for patients with arrhythmias, specifically with SVT. It also has some anti-adrenergic functions (think of it doing the opposite of everything coffee does), which can potentially have a beta-blocker like effect on ventricular arrhythmogenesis (Wilbur et al, 1997)
  • Magnesium has antiarrhythmic properties which are most pronounced in those arrhythmias where the mechanism involves early or delayed afterdepolarisations. It can be classified along with Class III and Class IV agents, as its effects are mainly involved in decreasing the duration of repolarisation by acting as an antagonist of potassium and calcium currents (Fazekas et al, 1993). By the same effect, it counteracts the depolarisation of pacemaker tissues, like a calcium channel blocker.

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